Sample preparing arrangement and a method relating to such an arrangement

ABSTRACT

The present invention relates to an arrangement (10, 20) for preparing samples (15, 27), submergible in a liquid medium. The arrangement comprises a section provided with a device (13, 23) for controllable generation of a magnetic field through influence of a control signal, said magnetic field being generated to trap at least part of said samples (15, 27).

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority under 35USC120 to U.S.application Ser. No. 09/938,471, filed Aug. 23, 2001, having the sametitle and inventors, which claims the benefit of U.S. Application No.60/228,015, filed Aug. 24, 2000, which are incorporated herein byreference.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to a chip-based method andarrangement for preparing, manipulating or detecting samples.

BACKGROUND OF THE INVENTION

[0003] There exists an enormous number of processes occurring in anorganism per unit time and also in each cell of the organism. One needstherefore fast techniques enabling acquisition of information inparallel, and effective means of storage and handling of suchinformation.

[0004] High throughput screening (HTS) examines in parallel as smallsamples as possible (so as not to use large amounts of expensive andrare chemicals) and as many of these as possible, usually arranged in adense, ordered solid-phase matrix, often referred to as a “chip”.

[0005] One example of such preparation is given in FIG. 1 (Biophotonics,January/February 2000, Univ. of Wisconsin, Franco Cerrina, et. al.).According to this technique, a matrix is created by burning awaydeposits from certain selected places on a chip, while depositingadditional chemicals on other places. This method, although fairly fastand cheap, produces a permanent pattern on a matrix, which will be usedup after single experiment. Thus, each new experiment requiresproduction of a new matrix.

[0006] The number of elements (spots) in a matrix varies depending onthe preparation method, but usually does not exceed 10,000, althoughmatrices as large as 1,000,000 sites have been reported. The outcome ofeach single “experiment” therefore gives at best 10,000 results. Inreality this number is much lower (around 20%) due to the very poorquality of even the best matrices produced to date.

[0007] Apart from preparation mentioned above a complete HTS-system hasto include also means of detection for the events taking place in eachspot as well as data transfer and evaluation.

[0008] Relevant literature includes: FR 2,781,886; U.S. Pat. Nos.5,874,219; 5,922,617; 5,755,942; WO 00/43534; WO 00/49382; WO 00/60356;and WO 00/54882.

SUMMARY OF THE INVENTION

[0009] One object of the invention is to present an arrangement whichimproves the “one by one” experimentation.

[0010] The technique allows a relatively rapid screening of newchemicals to be used as drugs, both with regard to their function and(importantly) with regard to the determination of the side effects thata given drug might exert, but can also be used in many otherapplications such as genome determination, proteomics and others.

[0011] In this invention, a different route as compared toabove-mentioned prior art is followed. The idea is not to prepare aready-to-use-product, which is impossible to modify, but to allow a userfor possibility to prepare its own “experiment”. Thus, one object of theinvention is to provide an easy-to-handle platform, which could be usedrepeatedly and could be prepared in-house. Consequently, the inventionis not limited to the surface deposits as are the devices describedabove (see also FIG. 1), but allows sample preparation either by surfacedeposition (at the bottom or at the walls of a crater) or by utilizingliquid state reactions allowing reagent contained in the liquid trappedwithin each well by a cap to mix with reagents contained in the liquidabove the craters by opening the “lids” (caps) at will.

[0012] In the arrangement according to the invention, it is relativelyeasy to change both the dimensions and the number of the wells. Also thesimplicity of the design will allow integrating the reaction productdetection system on-chip and perhaps also the facility for multi-welldeposition of the active substance.

[0013] Another object of the invention is to describe how the detectionlimits for the events under study can be improved using techniquessimilar to those used for chip production.

[0014] These objects are achieved by the initially mentionedarrangement, which comprises a section provided with a device forcontrollable generation of a magnetic field through influence of acontrol signal, said magnetic field being generated to trap at leastpart of said samples. Preferably, said device is a coil or amagnetically active material and it is made of an electricallyconducting material, preferably aluminium. Each device is appliedthrough a conductor of a current of different strength, whereby thecurrent amplitude and the number of windings in the coil areproportional to the strength of the magnetic field.

[0015] According to the first aspect of the invention the arrangementcomprises a cavity provided in a substrate and a lid for closing saidcavity. Preferably, the lid is a magnetic bead. The bead is directedonto a cavity using external magnets that create magnetic fieldscounteracting the field created by the material deposited around eachcavity. Each cavity is surrounded by a device, which directs said lidusing external magnets that create magnetic fields counteracting thefield created by material deposited around each cavity. The cavities areetched in a silicon surface and the lid is provided as a large magneticparticle in the liquid. The particle is attracted to a predeterminedcavity when the coil of said cavity is energised by electric current toproduce magnetic field of spatial attraction. Before sealing off thecavity, smaller magnetic particles are attracted into the cavity. Thesample is a magnetic particle covered with appropriate chemical(s). Inone embodiment, the arrangement comprises means for detection ofpresence of a magnetic capping lid capping a cavity. In one embodiment,the capping is detected by detecting the change in inductance in thecontrol circuit, which produces the attractive magnetic field, wherebythe bead acts like a magnetic yoke in a transformer, increasing theinductance. In another embodiment, the capping is detected throughdecrease of electromagnetic radiation to a detector inside the cavity orby changes of capacitance between electrodes inside the cavity or near acavity rim.

[0016] The arrangement may also comprise means for detection of changesof inductance when a magnetic particle passes through the opening intoor out of a cavity. The indication is determined using the direction ofan externally controlled magnetic field, either by changing thedirection of the electric current flowing through a coil or flipping anexternal magnet. Preferably, the particle contains particular molecularcoating, which reacts with the liquid in that cavity or with the coatingadsorbed on the walls of the cavity.

[0017] The substrate can be made of silicon, Si, or of Si-compound, suchas Si-oxide Si-nitride or Si-carbide, or combinations thereof, or asuitable polymer, such as polyethylene, polyethylene glycol,polyethylene oxide, fluorine containing a polymer (PTFE -Teflon), orsilicon containing a polymer.

[0018] According to a second aspect of the invention, the arrangementcomprises a member for generating acoustic waves and said device on asubstrate or carrier. The device and the member for generating acousticwaves are covered with an insulating layer. On the insulating layer, acombination of receptor-bead of a magnetisable material are attached. Asample is provided with a magnetic portion, which can be attractedtowards the receptor. The combination of receptor-bead attenuate theacoustic wave stronger than receptors attached to the insulating layer.Preferably, the surface of the insulating layer is inert to receptors,and the receptor-bead combination is attached to the surface by magneticforces acting on the bead.

[0019] The invention also relates to a method of preparing samples, bymeans of an arrangement submergible in a liquid medium, said arrangementcomprising a section provided with a device for generation of a magneticfield. The method comprises the steps of connecting a signal to saiddevice and generating a magnetic field to trap at least part of saidsamples. To each device is applied a current of different strength. Thearrangement is provided by a cavity in a substrate. The method comprisesthe further steps of arranging a magnetic lid for closing said cavity,directing said bead onto a cavity using external magnets that createmagnetic fields counteracting the field created by the materialdeposited around each cavity, and attracting smaller magnetic particlesinto the cavity before sealing off the cavity. Preferably, the sample isa magnetic particle covered with an appropriate chemical(s). Accordingto the method it is possible to detect presence of a magnetic cappinglid capping a cavity. The capping is determined by detecting the changein inductance in the control circuit, which produces the attractivemagnetic field, whereby the bead acts like a magnetic yoke in atransformer, increasing the inductance. The capping may also bedetermined through decrease of electromagnetic radiation to a detectorinside the cavity or by changes of capacitance between electrodes insidethe cavity or near the cavity rim. According to the method it ispossible to detect changes of inductance when a magnetic particle passesthrough the opening into or out of a cavity, and determining saidindication using the direction of an externally controlled magneticfield, either by changing the direction of the electric current flowingthrough a coil or flipping an external magnet.

[0020] According to the method, given a known number of samples in eachcavity and a density of respective coatings, quantitative data on thenumber of reaction between the coating on a wall of the cavity and thecoating on a small sample is obtained by counting the number of samples.

[0021] In particular aspects, the invention provides embodiments:

[0022] 1. An arrangement (10, 20) for preparing samples (15, 27),submergible in a liquid medium, characterised in, that the arrangementcomprises a section provided with a device (13, 23) for controllablegeneration of a magnetic field through influence of a control signal,said magnetic field being generated to trap at least part of saidsamples (15, 27).

[0023] 2. The arrangement according to embodiment 1, characterised in,that said device (13, 23) comprises a coil.

[0024] 3. The arrangement according to embodiment 1, characterised in,that said device comprises a magnetically active material.

[0025] 4. The arrangement according to any of preceding embodiments,characterised in, that the device comprises an electrically conductingmaterial, preferably aluminium.

[0026] 5. The arrangement according to any of preceding embodiments,characterised in, that each device through a conductor (17) is applied acurrent of different strength.

[0027] 6. The arrangement according to embodiment 2, characterised in,that a current amplitude and the number of windings in the coil areproportional to the strength of the magnetic field.

[0028] 7. The arrangement (10) according to any one of embodiments 1-6,characterised in that said arrangement comprises a cavity (12) providedin a substrate (11).

[0029] 8. The arrangement according to embodiment 7, characterised in,that it comprises a lid (14) for closing said cavity (12).

[0030] 9. The arrangement according to embodiment 8, characterised in,that said lid (14) is a magnetic bead.

[0031] 10. The arrangement according to embodiment 3 and 9,characterised in, that the bead is directed onto a cavity using externalmagnets that create magnetic fields counteracting the field created bythe material deposited around each cavity (12).

[0032] 11. The arrangement according to embodiment 9, characterised in,that said lid is a micro-bead introduced in said liquid medium.

[0033] 12. The arrangement according to embodiment 7, characterised in,that each cavity is surrounded by a device, which directs said lid usingexternal magnets that create magnetic fields counteracting the fieldcreated by material deposited around each cavity (12).

[0034] 13. The arrangement according to embodiment 7, characterised in,that the cavities are etched in a silicon surface and the lid isprovided as a large magnetic particle (14) in the liquid.

[0035] 14. The arrangement according to embodiment 13, characterised in,that said particle (14) is attracted to a predetermined cavity when thecoil of said cavity is energised by electric current to produce magneticfield of spatial attraction.

[0036] 15. The arrangement according to embodiment 14, characterised in,that before sealing off the cavity, smaller magnetic particles areattracted into the cavity.

[0037] 16. The arrangement according to any of preceding embodiments,characterised in, that said sample (15) is a magnetic particle coveredwith appropriate chemical(s).

[0038] 17. The arrangement according to any of preceding embodiments,characterised in, that the arrangement comprises means for detection ofpresence of a magnetic capping lid capping a cavity.

[0039] 18. The arrangement according to embodiment 17, characterised in,that said capping is detected by detecting the change in inductance inthe control circuit, which produces the attractive magnetic field,whereby the bead acts like a magnetic yoke in a transformer, increasingthe inductance.

[0040] 19. The arrangement according to embodiment 17, characterised in,that said capping is detected through decrease of electromagneticradiation to a detector inside the cavity or by changes of capacitancebetween electrodes inside the cavity or near a cavity rim.

[0041] 20. The arrangement according to any of preceding embodiments,characterised in, that it comprises means for detection of changes ofinductance when a magnetic particle passes through the opening into orout of a cavity.

[0042] 21. The arrangement according to embodiment 20, characterised in,that the indication is determined using the direction of externallycontrolled magnetic field, either by changing the direction of theelectric current flowing through a coil or flipping an externalmagnetic.

[0043] 22. The arrangement according to embodiment 20 or 21,characterised in, that said particle contains particular molecularcoating, which reacts with the liquid in that cavity or with the coatingadsorbed on the walls of the cavity.

[0044] 23. The arrangement according to any of embodiments 7-16,characterised in, that the substrate is made of silicon, Si, or ofSi-compound, such as Si-oxide Si-nitride or Si-carbide, or combinationsthereof, or a suitable polymer, such as polyethylene, polyethyleneglycol, polyethylene oxide, fluorine containing a polymer (PTFE-Teflon),or silicon containing a polymer.

[0045] 24. The arrangement according to any of embodiments 1-6,characterised in, that the arrangement (20) comprises a member (22) forgenerating acoustic waves and said device (23) on a substrate or carrier(21).

[0046] 25. The arrangement according to embodiment 24, characterised in,that the device and the member for generating acoustic waves are coveredwith an insulating layer (24).

[0047] 26. The arrangement according to embodiment 24, characterised in,that on the insulating layer, a combination of receptor-bead (25) of amagnetisable material is attached.

[0048] 27. The arrangement according to embodiment 26, characterised in,that a sample (27) is provided with a magnetic portion (28), which canbe attracted towards the receptor (25, 26).

[0049] 28. The arrangement according to embodiment 26, characterised in,that said combination of receptor-bead attenuate the acoustic wave (29)stronger than do receptors attached to the insulating layer (24).

[0050] 29. The arrangement according to any of embodiments 25-28,characterised in that said surface of the insulating layer (24) is inertto receptors, and that the receptor-bead combination is attached to thesurface by magnetic forces acting on the bead.

[0051] 30. A method of preparing samples (15, 27), by means of anarrangement (10, 20) submergible in a liquid medium, said arrangementcomprising a section provided with a device (13, 23) for generation of amagnetic field, characterised by connecting a signal to said device (13,23) and generating a magnetic field to trap at least part of saidsamples (15, 27).

[0052] 31. The method of embodiment 30, characterised in that to eachdevice is applied a current of different strength.

[0053] 32. The method of embodiment 30, characterised in that saidarrangement is provided by a cavity (12) in a substrate (11).

[0054] 33. The method of embodiment 32, characterised by arranging amagnetic lid (14) for closing said cavity (12).

[0055] 34. The method of embodiment 33, characterised by directing saidbead onto a cavity using external magnets that create magnetic fieldscounteracting the field created by the material deposited around eachcavity (12).

[0056] 35. The method according to any of embodiments 30-34,characterised by attracting smaller magnetic particles into the cavitybefore sealing off the cavity.

[0057] 36. The method according to any of embodiments 30-34,characterised in that said sample is a magnetic particle covered with anappropriate chemical(s).

[0058] 37. The method according to any of embodiments 30-35,characterised by detection of presence of a magnetic capping lid cappinga cavity.

[0059] 38. The method according to embodiment 37, characterised bydetecting said capping by detecting the change in inductance in thecontrol circuit, which produces the attractive magnetic field, wherebythe bead acts like a magnetic yoke in a transformer, increasing theinductance.

[0060] 39. The method according to embodiments 37, characterised bydetecting said capping through decrease of electromagnetic radiation toa detector inside the cavity or by changes of capacitance betweenelectrodes inside the cavity or near the cavity rim.

[0061] 40. The method according to any of preceding embodiments,characterised by detection of changes of inductance when a magneticparticle passes through the opening into or out of a cavity.

[0062] 41. The method according to embodiment 40, characterised bydetermining said indication using the direction of externally controlledmagnetic field, either by changing the direction of the electric currentflowing through a coil or flipping an external magnetic.

[0063] 42. The method according to any of embodiments 30-41,characterised by given a known number of samples in each cavity and adensity of respective coatings, quantitative data on the number ofreaction between the coating on a wall of the cavity and the coating ona small sample is obtained by counting the number of samples.

BRIEF DESCRIPTION OF THE DRAWINGS

[0064] In the following, the invention will be further described in anon-limiting way under reference to the accompanying drawings in which:

[0065]FIG. 1 shows an arrangement according to prior art,

[0066]FIG. 2 is a schematic view from above of chip according to theinvention,

[0067]FIG. 3 is a schematic view, showing an enlarged cross-sectionalong line II-II through a part of the chip according to FIG. 2,

[0068]FIG. 4 is a schematic view from above of a part of another chipaccording to the invention, and

[0069]FIG. 5 is a schematic view, showing an enlarged cross-sectionalong line IV-IV through a part of the chip according to FIG. 4.

[0070]FIG. 6 is a schematic view, showing an enlarged cross-section of aportion of FIG. 5 under (A) no magnetic field, (B) an attractive field,and (C) a repulsive field.

DETAILED DESCRIPTION OF THE PARTICULAR EMBODIMENTS

[0071] The basic idea of the present invention is to create an enclosureor a crater (a well), provided with a lid, which can be opened andclosed by a “lid”. A user can control the lid and the device is intendedto be submerged in a liquid medium. By operating the lid, the enclosedvolume becomes separated from the surroundings. That means, the liquidstored in the crater, particles suspended therein, and/or material thatadheres to the craters' inner surface are not affected by subsequentchanges that occur in the surroundings while the lid is closed. Thesechanges might be a different chemical composition of the liquid, lightshining on the crater chip, or other solids in the surrounding liquid.The lid may or may not be completely liquid-tight, but mixing of theliquid outside a crater with the liquid contained inside a well will bedramatically slowed. Hence, solids and liquids will be well separatedbetween inside and outside, by the lid.

[0072]FIGS. 2 and 3 illustrate a first example of an arrangementaccording to the invention. FIG. 2 illustratess an enlarged schematicview of a part of chip 19 comprising a number of sample collectingarrangements 10. Each sample collecting arrangement comprises a cavity(crater, pocket, well) 12 provided in a substrate 11 and means 13 tocontrol the cap (lid, cover) 14. Each control means 13 is connected tocontroller 18 (FIG. 3) through connections 17. An insulating layer (111)and an on-chip detector (112) are also shown.

[0073]FIG. 3 is a schematic cross-section through the device 10.However, the device 10 is shown in a stage where samples 15 arecollected and the crater 12 is closed by means of the lid or closure 14.The samples in this particular case are magnetic particles ofdiameter(s) much smaller than the diameter of the lid, covered withappropriate chemical(s)

[0074] In this embodiment, the lid control means 13 compriseelectrically actuated coils and the lid 14 is a magnetizeable bead.

[0075] By making many craters 12, all with individually controlled lids14, different types of mixing of solids dispensed in a liquid and/orliquids can be achieved at the same time. As different liquids/solidsare introduced to the outside of the craters only user-selected craterswith open lids will be reached for the mixing by the liquids/solidsexternal to the closed craters.

[0076] The dimensions and the shapes of each crater 12 can of coursevary within a large interval both with respect to its diameter anddepth. The craters can have circular cross-section, e.g. having about 50μm deep with the diameters of approximately 100 μm. It is relativelyeasy to produce craters with dimensions ranging from few μm and largerand with depth ranging from few μm and up to several hundreds of μm,having, e.g. square shapes.

[0077] The material of the substrate can be silicon and themanufacturing process may include micro-machining, similar to theprocess of making microprocessors or memories chips. A device maycontain from several hundreds of craters on a single piece of silicon,providing a so-called chip. Of course tens of thousands of craters oncommercial units can be arranged.

[0078] Preferably, the lid is a micro-bead introduced in a liquid. Thelid-actuation mechanism, i.e. the closing and the opening of each of thecraters is performed using switchable magnetic fields that influence themotion of the introduced beads. The magnetic fields are created usingthe coils 13 deposited around each crater.

[0079] The coils 13 surrounding each of the craters are made of anelectrically conducting material. In the preferred embodiment theconductor is made of aluminium, Al, but any electrical conductor can beused. Preferably, each coil is accessible through electricallyconducting leads so that a current of different strength can be appliedseparately to each coil. The current amplitude and the number ofwindings in the coil are proportional to the strength of the magneticfield, which can thus be varied. Clearly, it is possible to change thenumber of windings in the coils surrounding each crater as well as theirwidth and thickness within a broad range of dimensions. Preferably butnot exclusively, coils can have from 2 and up to 10 windings.

[0080] In an alternative embodiment, instead of the coils 13, thecontrol means can be substituted by a magnetically active materialsurrounding each crater and direct the beads using external magnets thatwill create magnetic fields counteracting the field created by thematerial deposited around each crater 12.

[0081] Preferably, the craters are etched in the silicon surface and thelid is provided by a large magnetic particle 14 in the liquid. Thus,particle 14 can be attracted to the crater of choice when the coil ofthis crater is energised by electric current to produce magnetic fieldfor spatial attraction. Before sealing off the crater of choice,however, it is also possible to attract smaller magnetic particles intothe crater. To attract the smaller magnetic particles 15 to the craterwe energize the coil by leading electric current through it. When thecoil is energized, a magnetic field is established. This field willattract the magnetic particle 15 from the liquid. These smallerparticles have higher mobility in the liquid compared to the mobility oflarger particles and will thus reach crater faster than the larger lids.The large lid-particle will cap the crater at a later stage. Preferably,as large particles commercially available magnetic particles such asferromagnetic or super-paramagnetic having about 100 micrometers in sizecan be used, while the size of the smaller particles is much smallerthan the crater's size. There are other dimensions and particle types onthe market and the invention is applicable to a broad range of particlesizes, shapes and materials.

[0082] To open a closed crater, a repelling field is generated eitherexternally or by inverting the direction of the current flowing throughthe coil. It is also possible to terminate the current through the coil,whereby the particle may be released due to shear force from the flowingliquid or due to gravitational forces if the craters are positioned“upside down”.

[0083] The simple actuation of the crater lid using current controlledmagnetic field(s) and the large number of craters on a chip makes itnecessary that the chip is operated automatically through controllingarrangement. The chip is preferably provided with an interface devicethat establishes electrical connection with the chip and provides thehandling of the surrounding fluid with the beads and chemicals. Afteruse the chip may be removed for cleaning and reuse or disposal. Theinterface device will be connected to a computer equipped with suitablesoftware to control the sequence of operations on the craters and theliquid handling system. The software will also provide an interface forthe user to establish the process sequence and to plan the states of thecrater lids in each sequence.

[0084] Detection of a magnetic capping bead can also be done. It isimportant to obtain feedback on which craters are capped. The presenceof a magnetic capping bead, in place over a crater, can be detected bythe change in inductance in the electric circuit, which produces theattractive magnetic field. The bead acts like a magnetic yoke in atransformer, increasing the inductance. A resonant, or other, circuitcan then detect this inductance change.

[0085] The presence of the capping bead can be detected by various otherschemes, like the decrease of electromagnetic radiation to a detectorinside the crater or by changes of capacitance between electrodes insidethe crater or near the crater rim.

[0086] Another possible application along similar lines is the detectionof changes of inductance when a small magnetic sphere passes through theopening into a well. Using the arrangement according to the invention itis possible to determine whether a sphere is entering the well or if itis leaving the well. This is determined using the direction ofexternally controlled magnetic field (either by changing the directionof the electric current flowing through a coil or flipping an externalmagnetic field creating device by other means). Such a sphere maycontain particular molecular coating, which will react with the liquidin that well or with the coating adsorbed on the walls of the crater.Given one knows the number of spheres in each well and the density ofthe respective coatings quantitative data on the number of reactionbetween the coating on the wall and the coating on a small bead can beobtained by simply counting the spheres.

[0087] Following non-limiting examples are given for simplifying theunderstanding of the invention: According to a first example liquid Acontaining magnetic beads is introduced. User selected craters 12 areenergized and hence capped. The remaining beads are flushed away with acleaning liquid. Now liquid B is introduced, containing small (muchsmaller than the capping beads) particles, called X, made of a materialinteresting to the user. Only uncapped craters will accept X. Then, moremagnetic beads are introduced and selected craters are capped, trappingX. Cleaning liquid will flush all excess away. A liquid containingchemical reagent Y can then be introduced and some craters are opened. Xand Y are allowed to mix and react, but only in the user-selected areas.This reaction can be followed using sensing techniques, which can easilybe incorporated into the system, for example using optical techniques.Other possible novel detection techniques easily incorporated into thepresent embodiment are mentioned below.

[0088] In a second example, a substance is attached to the craters innersurface. In a repeating sequence some craters are closed by the beadsand the others are exposed to a reactive chemical A. After the reactionthe chemical is flushed and some craters are exposed to another chemicalB. So there will be craters that have been exposed to A and B, some toA, some to B, and some to neither. This process can be repeated withmany chemicals producing very large numbers of differently modifiedsubstances residing in different locations (craters) of choice. With asequence of 10 different chemicals, for example, more than 1000different combinations are obtained. In particular, this could be usedto synthesize DNA strands or (using appropriate well-known techniques)to investigate the function(s) of different proteins.

[0089] Yet another application is to lock cells in the wells filled withdifferent chemicals and monitor the reaction of cells (cellproliferation, differentiation, spreading or others) to thesechemistries. This would enable, for example a fast high throughputscreening of drugs.

[0090] The arrangement may also be used separately, one-by-one, forexample to deliver a certain chemical or chemicals locally at a certainplace or places in a reaction vessel, and monitor reaction productslocally, or to deliver a drug inside a body.

[0091] Another field of possible applications of the device has beentriggered by something generally referred to as a “low throughputscreening” (LTS). LTS is often used when the amount of requiredinformation is smaller but in addition one wants to obtain somequantitative information about concentrations of analyses or number ofreactions that occur during certain time at certain amounts of reagents.The idea behind LTS has much in common with another timely idea oftenused to day: an “electronic tongue”. Electronic tongue is a device thatenables one to determine components in a liquid. These components canthen be associated with certain tastes (sweet, sour, salt, etc. orcombinations thereof). To determine the content of simple liquids in aliquid mixture, for example % of sugar dissolved in a cup of tea alongwith the amount of tea used to prepare this cup, and even perhapsdifferent tea blends used. To acquire knowledge about all these requiresperforming several experiments with constituents that react differentlyto different tea blends and to different amounts of tea from each blendthat has been used, as well as to the amounts of sugar being dissolvedin this tea. All these can be made by LTS methods using our equipmentand choosing appropriate reagents different for each crater and lettingthese first to react with a “standard” samples (“learning the tongue” torecognise certain non-mixed liquids) and later exposing these samples tomixtures of different tea blends with or without sugar. Appropriate dataprocessing from the outcome compared with the results obtained onstandard samples enables one often to obtain information about teablends used and the amount of sugar dissolved.

[0092] The device is not limited to spheres or coils for creation ofmagnetic fields that direct beads nor is it limited to the use of beads,and other shapes can be used. Finally it is not limited to the use ofsilicon technology to fabricate the crater matrices; other materials canbe used for this purpose.

[0093] Following are additional, non-limiting, examples of differentcrater preparation techniques and materials of use paired with itsutilisation:

[0094] The general idea behind these examples is to manipulate smallparticles in order to bring them to a chosen place on the surface of thesubstrate using magnetic field(s) as a driving force for particlemanipulation. The surface of the substrate may be either patterned in aparticular manner, or not. When the substrate is patterned and thepattern consists of craters some particles are used preferably as capsor lids to close each crater as described earlier. When the substrate isleft without a pattern or patterned in a different manner (see below foran example) the particles can be used mainly as a way to enhancesensitivity of detection of the processes taking place in the device.

[0095] The magnetic force to manipulate the particles can be createdusing coils as described above, but it also may be created usingexternally applied magnets. In the former case the field strength (andthus the magnitude of the force) is determined primarily by the numberof windings in the coil and the magnitude of the electric current. Inthe latter case it is possible to control the magnitude of the magneticforce by appropriate choice of magnet position and strength.

[0096] The substrate may be made of silicon (described above), Si, or ofSi-compound, e.g. Si-oxide Si-nitride or Si-carbide, or combinationsthereof. It may also consist of thin self-supporting Si, or of a Si-compound, with another film of suitable thickness (for example fewmicrometers), such as ZnO, evaporated onto its surface. This additionalfilm is needed if the device is to work as an acoustic wave device fordetection.

[0097] The substrate may also be fabricated using other material thansilicon. For example a suitable polymer, e.g. polyethylene, polyethyleneglycol, polyethylene oxide, fluorine containing a polymer (PTFE-Teflon),or silicon containing a polymer, may be used as a substrate material.

[0098] When patterning the substrate different techniques may be useddepending on the substrate material and the pattern. Thus, Si andSi-compounds are suitably patterned applying well-known techniques fromthe semiconductor fabrication. When patterning polymers one can useknown techniques like polymer stamping or moulding.

[0099] The patterns on the substrate are not limited to craters. Forexample when using the device as an acoustic wave detector one mayproduce matrices consisting of many interdigitated patterns needed foracoustic wave generation and detection. FIGS. 4 and 5 show one exampleof such a device.

[0100] The coils can be patterned using well-known techniques such aselectroplating, vapour deposition or sputter.

[0101] In the following, few non-limiting examples of how similartechniques based on the magnetic manipulation of beads can be used toenhance detection sensitivity of chemical reactions are described:

[0102] A single site of a matrix of the Surface Acoustic Wave, SAW,devices is shown in FIGS. 4 and 5 Each device 20, comprises anarrangement 22 for generating acoustic waves and magnetic field controlmeans 23 on a substrate or carrier 21. The arrangement for generationand detection of acoustic waves comprises two finger-shaped, reversedarranged conductors 221 and 222 provided on both sides of the controlmeans 23. The control means 23 is arranged as a coil connected to acontroller (not shown) as described in conjunction with foregoingembodiment. The coil and the arrangement for generating acoustic wavesare covered with an insulating layer 24 (FIG. 5), made of, e.g. glass orplastic, or a biomolecular layer. Onto this insulating layer,(biomolecular) “receptors” 25 can be adsorbed. The receptors, 25, can beused in their native state and adsorb spontaneously onto a suitablyprepared insulating layer, 24. They may also be pre-adsorbed onto smallmagnetic beads, 28, and the whole complex (magnetic bead-receptor) canbe attracted to the surface of the SAW—device by magnetic field createdby letting the current pass through the coil 23. The beads +receptorsattenuate the acoustic wave, 29, many times stronger compared to thecase when native receptors are attached to the insulating layer 24 andthus much lower concentrations of adsorbates at the surface are neededwhen the receptor-bead complexes are adsorbed.

[0103] Another advantage of such configuration is that it allows for theregeneration of the device. It may be possible to manufacture thesurface of the insulating layer, 24, inert to receptors themselves, sothat the receptor and bead complex is attached to the surface bymagnetic forces acting on a bead. Once the investigation is completedthe magnetic field can be removed (or the direction of the field changedusing external magnet) causing the receptor and bead complex to desorb.This will leave the surface in its as-prepared state ready for anotherinvestigation.

[0104] If one wishes to study the reaction between these receptors andappropriate “donors”, 27, the latter may be introduced in their nativestage (27), or coupled to a magnetic bead 28.

[0105] Again, coupling the donors to magnetic beads allows for largerattenuation of acoustic wave when the acceptor-donor reaction hasoccurred (irrespective from whether this reaction caused additionaldonor-derived beads to be adsorbed on the surface or whether it causedthe desorption of the reaction product−receptor+bead/donor+bead) whichdecreases the necessary number of reaction needed for a givensensitivity of the device.

[0106] Since the beads influence the propagation of acoustic wavesstronger than do the molecules, which react, to each other one obtainsmanifold enhancement of the detection of the chemical reaction involvingthese molecules. One particular, but far from the only one, example ofsuch reaction is the antibody-antigene reaction. Another example wouldbe DNA-complementary DNA (or PNA) reaction. The reaction may occurspontaneously over many sites of the matrix, leaving other sitesunreacted. By separately applying the magnetic field so as to removeparticles from each site one obtains (i) a pattern over sites wherereaction did take place, and (ii) a quantitative information about thenumber of reaction that did take place at each site (see, FIGS. 6A-6C).

[0107] Another way to use the matrix with interdigitated electrodes isas a capacitor; a certain number of electrode pairs will be consideredas a single site and will constitute a capacitor. One prepares each siteof the matrix differently, i.e. using different chemistries. Bydirecting beads, with specific molecules attached to them, to thesesites using magnetic field, or withdrawing particles from these sites,one is able to perturb the dielectric constant of a layer close to thesurface and therefore produce large changes of the capacitance of thedevice compared to attachment of only (bio)molecules.

[0108] The invention is not limited the shown embodiments but can bevaried in a number of ways without departing from the scope of theappended claims and the arrangement and the method can be implemented invarious ways depending on application, functional units, needs andrequirements etc.

What is claimed is:
 1. A microelectromechanical system which uses anordered array of magnetically controlled beads to regulate localizationof discrete fractions of a fluid medium at discrete, predeterminedelements of a substrate, said system comprising: a substrate comprising(a) a surface in contact with a fluid medium and (b) an ordered array ofa plurality of elements, each element comprising a discrete place on thesurface: means for generating controllable, localized magnetic fields ateach element; a plurality of beads, each disposed in the mediumproximate to a corresponding element: means for trapping the fractionwith the beads; a controller operably coupled to the localized magneticfields generating means: wherein the localized magnetic fieldsgenerating means controllably generates magnetic fields throughinfluence of control signals generated by the controller, wherein saidmagnetic fields magnetically move each bead relative to thecorresponding element, and thereby regulate localization of discretefractions of the medium at discrete, predetermined elements of thesubstrate.
 2. A system according to claim 1, which uses an ordered arrayof magnetically controlled beads to regulate localization of discretefractions of a fluid medium at discrete, predetermined elements of asubstrate, said system comprising: a substrate comprising (a) a surfacein contact with a fluid medium and (b) an ordered array of a pluralityof elements, each element comprising a discrete place on the surface anda corresponding integrated magnetic field generating device, a pluralityof beads, each disposed in the medium proximate to a correspondingelement and adsorbing a discrete fraction of the fluid medium, acontroller operably coupled to each device; wherein each devicecontrollably generates magnetic fields through influence of controlsignals generated by the controller, wherein said magnetic fieldsmagnetically move each bead relative to the corresponding element, andthereby regulate localization of discrete fractions of the medium atdiscrete, predetermined elements of the substrate.
 3. A system accordingto claim 2, wherein each element further comprises an on-chip detectorsensitive to the proximity to the element of the bead or the fraction.4. A system according to claim 2, wherein the fractions comprise agentspresent in the medium, wherein the agents are selected from the groupconsisting of optionally derivatized magnetic particles, chemicals andcells.
 5. A system according to claim 2, wherein the localization isquantitative.
 6. A system according to claim 2, wherein each elementfurther comprises a discrete cavity in the surface, wherein saidmagnetic fields independently, magnetically move each bead between anuncapped position, opening the corresponding cavity to a fraction of themedium and a capped position, restricting the cavity to the fraction ofthe medium, and thereby regulate localization of discrete fractions ofthe medium at discrete, predetermined elements of the substrate.
 7. Amicroelectromechanical system which uses an ordered array ofmagnetically controlled beads to regulate localization of discretefractions of a fluid medium at discrete, predetermined elements of asubstrate, said system comprising: a substrate comprising (a) a surfacein contact with a fluid medium and (b) an ordered array of a pluralityof elements, each element comprising a discrete place on the surface anda corresponding magnetically active material, a plurality of beads, eachdisposed in the medium proximate to a corresponding element andadsorbing a discrete fraction of the fluid medium, a plurality ofmagnets external to the substrate; a controller operably coupled to theexternal magnets; wherein the external magnets controllably generatemagnetic fields through influence of control signals generated by thecontroller, wherein said magnetic fields magnetically move each beadrelative to the corresponding element, and thereby regulate localizationof discrete fractions of the medium at discrete, predetermined elementsof the substrate.
 8. A system according to claim 7, wherein each elementfurther comprises an on-chip detector sensitive to the proximity to theelement of the bead or the fraction.
 9. A system according to claim 7,wherein the fractions comprise agents present in the medium, wherein theagents are selected from the group consisting of optionally derivatizedmagnetic particles, chemicals and cells.
 10. A system according to claim7, wherein the localization is quantitative.
 11. A system according toclaim 7, wherein each element further comprises a discrete cavity in thesurface, wherein said magnetic fields independently, magnetically moveeach bead between an uncapped position, opening the corresponding cavityto a fraction of the medium and a capped position, restricting thecavity to the fraction of the medium, and thereby regulate localizationof discrete fractions of the medium at discrete, predetermined elementsof the substrate.
 12. A system according to claim 1, which uses anordered array of magnetically controlled beads to regulate localizationof discrete fractions of a fluid medium at discrete, predeterminedelements of a substrate, said system comprising: a substrate comprising(a) a surface in contact with a fluid medium and (b) an ordered array ofa plurality of elements, each element comprising a discrete cavity inthe surface and a corresponding integrated magnetic field generatingdevice, a plurality of beads, each disposed in the medium proximate to acorresponding cavity, a controller operably coupled to each device;wherein each device controllably generates magnetic fields throughinfluence of control signals generated by the controller, wherein saidmagnetic fields independently, magnetically move each bead between anuncapped position, opening the corresponding cavity to a fraction of themedium and a capped position, restricting the cavity to the fraction ofthe medium, and thereby regulate localization of discrete fractions ofthe medium at discrete, predetermined elements of the substrate.
 13. Asystem according to claim 12, wherein each element further comprises anon-chip detector sensitive to the proximity to the element of the beador the fraction.
 14. A system according to claim 12, wherein thefractions comprise agents present in the medium, wherein the agents areselected from the group consisting of optionally derivatized magneticparticles, chemicals and cells.
 15. A system according to claim 12,wherein the localization is quantitative.
 16. A system according toclaim 12, wherein the fractions comprise agents present in the medium,the agents are optionally derivatized magnetic particles, and themagnetic fields, in conjunction with movement of the bead, controllablymove one or more of the particles into or out of the cavity.
 17. Amicroelectromechanical system which uses an ordered array ofmagnetically controlled beads to regulate localization of discretefractions of a fluid medium at discrete, predetermined elements of asubstrate, said system comprising: a substrate comprising (a) a surfacein contact with a fluid medium and (b) an ordered array of a pluralityof elements, each element comprising a discrete cavity in the surfaceand a corresponding magnetically active material, a plurality of beads,each disposed in the medium proximate to a corresponding cavity, aplurality of magnets external to the substrate; a controller operablycoupled to the external magnets; wherein the external magnetscontrollably generate magnetic fields through influence of controlsignals generated by the controller, wherein said magnetic fieldsindependently, magnetically move each bead between an uncapped position,opening the corresponding cavity to a fraction of the medium and acapped position, restricting the cavity to the fraction of the medium,and thereby regulate localization of discrete fractions of the medium atdiscrete, predetermined elements of the substrate.
 18. A systemaccording to claim 17, wherein each element further comprises an on-chipdetector sensitive to the proximity to the element of the bead or thefraction.
 19. A system according to claim 17, wherein the fractionscomprise agents present in the medium, wherein the agents are selectedfrom the group consisting of optionally derivatized magnetic particles,chemicals and cells.
 20. A system according to claim 17, wherein thelocalization is quantitative.
 21. A system according to claim 17,wherein the fractions comprise agents present in the medium, the agentsare optionally derivatized magnetic particles, and the magnetic fields,in conjunction with movement of the bead, controllably move one or moreof the particles into or out of the cavity.
 22. A method of using asystem according to claim 2, comprising the step of controllablygenerating magnetic fields through influence of control signalsgenerated by the controller, wherein said magnetic fields independently,magnetically move each bead relative to the corresponding element, andthereby regulate localization of discrete fractions of the medium atdiscrete, predetermined elements of the substrate.
 23. A method of usinga system according to claim 7, comprising the step of controllablygenerating magnetic fields through influence of control signalsgenerated by the controller, wherein said magnetic fields independently,magnetically move each bead relative to the corresponding element, andthereby regulate localization of discrete fractions of the medium atdiscrete, predetermined elements of the substrate.
 24. A method of usinga system according to claim 12, comprising the step of controllablygenerating magnetic fields through influence of control signalsgenerated by the controller, wherein said magnetic fields independently,magnetically move each bead between an uncapped position, opening thecorresponding cavity to a fraction of the medium and a capped position,restricting the cavity to the fraction of the medium, and therebyregulate localization of discrete fractions of the medium at discrete,predetermined elements of the substrate.
 25. A method of using a systemaccording to claim 17, comprising the step of controllably generatingmagnetic fields through influence of control signals generated by thecontroller, wherein said magnetic fields independently, magneticallymove each bead between an uncapped position, opening the correspondingcavity to a fraction of the medium and a capped position, restrictingthe cavity to the fraction of the medium, and thereby regulatelocalization of discrete fractions of the medium at discrete,predetermined elements of the substrate.